The ZERO Childhood cancer program is Australia's national precision medicine program for paediatric cancer. ZERO has shown that comprehensive genomic analysis and the early use of targeted therapies guided by this analysis, can dramatically alter the survival if children with high-risk cancer. The basis of this improvement is the informed addition of targeted therapies directed against driver lesions within that individual's cancer. Finding NTRK fusions in precision medicine programs like ZERO often causes much excitement, because it means that there are very effective drugs available. But what to do when something new is discovered in the cancer genome, like the NTRK2 internal tandem duplication (NTRK2-ITD) we identified in ZERO? Is this really a driver? Would a cancer with such a lesion respond to a TRK inhibitor? In our report in npj Precision Oncology (linked here), we have shown that NTRK2-ITD is constitutively active, independent of ligand and able to drive cytokine independent proliferation and repress cell death. This is all the more remarkable because this is not a duplication of the Tyrosine Kinase domain, but instead a duplication of the transmembrane domain (Figure 1A and B).

NTRK2-ITD does not function exactly like a fusion, as it is a membrane bound oncoprotein, and it seems likely that a tyrosine residue in the duplicated section, now located intracellularly, results in a conformational change that favours transphosphorylation and activation of NTRK2 (Figure 1C). That possibility is still up for debate. What is not questionable is that  NTRK2-ITD signalling can be effectively blocked by existing TRK inhibitor drugs. The implications are important. First, patients with tumours bearing NTRK-ITDs could benefit significantly from the addition of TRK inhibitors to their treatment regimens. However, standard testing would not necessarily detect these lesions, because they are designed to find NTRK fusions. Even if identified, the primary indication for TRK inhibitors - NTRK fusions - means that patients with ITDs might not have the choice to receive these therapies. An important purpose of our work to define the biology of ITDs involving NTRK2, is to help make the case for the inclusion of these lesions in the indications for TRK inhibitors. To be sure, NTRK-ITDs are rare, but they are recurrent. Learning how patients with these drivers respond to targeted therapy is the next step.